Abstract

Surgery remains the most successful curative treatment for cancer. However, some patients with early-stage disease who undergo surgery eventually succumb to distantmetastasis. Here, we show that in response to surgery, the lungs become more vulnerable to metastasis due to extracellular matrix remodeling. Mice that undergo surgery or that are preconditioned with plasma from donor mice that underwent surgery succumb to lung metastases earlier than controls. Increased lysyl oxidase (LOX) activity and expression, fibrillary collagen crosslinking, and focal adhesion signaling contribute to this effect, with the hypoxic surgical site serving as the source of LOX. Furthermore, the lungs of recipient mice injected with plasma from post-surgical colorectal cancer patients are more prone to metastatic seeding than mice injected with baseline plasma. Downregulation of LOX activity or levels reduces lung metastasis after surgery and increases survival, highlighting the potential of LOX inhibition in reducing the risk of metastasis following surgery.

This work is primarily supported by the European Research Council (grant 260633, Y.S.) and Rappaport Institute (Y.S. and P.H.) J.M. was supported by the Academy of Finland Center of Excellence (grant 251314), the S. Juselius Foundation, and the Jane and Aatos Erkko Foundation. F.B. is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC).